From 1979 to 1999, total injury mortality rates declined overall in the United States, despite increases in suicide rates in the late 1980s and in homicide rates in the early 1990s (CDC, unpublished data, 2007). From 1999 to 2004, however, total injury mortality rates increased 5.5%, from 53.3 to 56.2 per 100,000 population, the first sustained increase in 25 years. To assess this increase, CDC analyzed the most recent data from the National Vital Statistics System (NVSS). This report summarizes the results of that analysis, which determined that U.S. mortality rates increased from 1999 to 2004 for unintentional injuries, suicides, and injuries of undetermined intent; homicide rates were stable. Among persons aged 45-54 years, the total injury mortality rate increased 24.5%, including an 87.0% increase in the mortality rate from unintentional poisoning (most commonly drug poisoning) and a 48.0% increase in suicide by hanging/suffocation. Among persons aged 20-29 years, the total injury mortality rate increased 7.7%, including a 92.5% increase in the death rate from unintentional poisoning and a 31.7% increase in suicide by hanging/suffocation. Parallel increases in multiple categories and mechanisms of injuries within these two age groups suggest an increase in one or more shared risk factors (e.g., drug abuse); prevention programs that focus on shared risk factors might help reduce deaths from injuries.